Are You Confident of the Diagnosis?

Allogeneic hemopoietic stem cell transplantation (AHSCT) is a therapeutic tool that is being used with increasing frequency. The number of centers that perform AHSCT and the number of transplant patients is rising, with more than 20,000 transplants performed yearly worldwide. The main complication of AHSCT is the development of graft versus host disease (GVHD). The result is an increased exposure of dermatologists to these patients in their clinics.

GVHD is divided into two forms: acute GVHD and chronic GVHD.

Acute GVHD (AGVHD) usually appears in the first 2 to 6 weeks after the transplant, but cases of late AGVHD are more frequent with the increased use of nonablative AHSCT. AGVHD is similar to a drug eruption. It has five target organs: skin, gastrointestinal tract, liver, lung, and lymphoid tissue. AGVHD is similar to a drug eruption. The dermatological clinical spectrum is from morbilliform exanthema to epidermal necrolysis (Figure 1).

Figure 1.

Acute GVHD with some erosions suggesting evolution to stage IV.

Chronic GVHD (CGVHD) usually occurs a few months after the transplant, but may happen earlier in patients after a second (or more) AHSCT, or after donor lymphocyte infusions. It is similar to an autoimmune connective tissue disease. CGVHD may occur as a progression from active AGVHD, quiescent (when there is a disease-free interval between AGVHD and CGVHD) and de novo (in patients without previous AGVHD).

The target organs for CGVHD are the skin, liver, eyes, upper respiratory tract, esophagus, lower gastrointestinal tract, and skeletal muscle. Dermatologically, CGVHD is divided into two clinical forms: lichenoid GVHD, which appears early in the evolution (Figure 2) and sclerodermatous GVHD, which appears later (Figure 3). The expanded spectrum of sclerodermoid involvement includes lichen sclerosus, morphoea, panniculitis, and fasciitis.

Figure 2.

Lichenoid chronic GVHD.

Figure 3.

Sclerodermatous GVHD.

What you should be alert for in the history

AGVHD

In AGVHD, the skin is often the first and most commonly involved organ. The patient may have a prodrome of an itchy and burning sensation, followed by a maculopapular exanthem that appears at 2-6 weeks after the AHSCT. Hyperacute GVHD appears in the first 14 days, but always after engraftment has commenced; while late AGVHD may be observed as late as 192 days after AHSCT.

AGVHD may begin on the pinnae, cheeks, lateral neck, upper back, and palms and soles. The erythematous macules may coalesce to cover the whole body. Eventually, the skin desquamates and leaves postinflammatory pigmentary changes.

CGVHD is the most common complication after transplantation, described in 60%-80% of patients. Lichenoid CGVHD appears before the first year in more than 50% of the patients. Sclerodermatous lesions usually appear after day 500 following AHSTC.

- Lungs—wheezing, dyspnea, and chronic cough that is unresponsive to bronchodilator therapy

Characteristic findings on physical examination

AGVHD

The general condition will depend on the stage of GVHD. Maculopapular exanthem with early lesions centered on hair follicles (clue to the diagnosis) is the most common presentation. Sometimes the exanthem may evolve into erythroderma (stage III). Approximately 2% of cases develop vesicles, epidermal necrosis with positive Nikolsky sign, and general erythroderma, resembling toxic epidermal necrolysis (stage IV disease).

Other rare forms include scarlatiniform, varicelliform, and ichthyosiform eruptions.

Extracutaneous clinical signs will depend on the organ involved. The severity of AGVHD is graded by measuring skin, liver, and gastrointestinal involvement.

The stages of AGVHD are summarized in Table I.

Table I.

The stages of AGVHD.

Organ

Stage I

Stage II

Stage III

Stage IV

Skin

Maculopapular rash involving 25% of the body

Maculopapular rash involving 25%-50% of the body

Generalized erythroderma

Toxic epidermal necrolysis appearance

Bilirubin levels (umol/L)

34-51

51-101

101-256

>256

Diarrhea

500-1000mL/day

1000-1500mL/day

>1500mL/day

>2000mL/day or severe abdominal pain with or without diarrhea

CGVHD

The physical findings of CGVHD depend on the clinical form.

Lichenoid CGVHD presents with lichen-planus-like lesions. These may include erythematous or violaceous papules or plaques, sometimes able to form larger confluent areas. They are usually not well-defined. The periorbital region, ears, axillae, and flexures (especially axillary and inguinal regions) are the most commonly affected sites. In some cases, lichenoid papules can occur around hair follicles. Lichenoid CGVHD can also affect the nails and the genital organs.

Sclerodermatous CGVHD presents with lichen sclerosus, morphea, fasciitis, and systemic scleroderma-like lesions. These may include indurated sclerotic shiny white-yellow plaques of poorly defined contours, usually with the early development of patchy hyperpigmentation or a poikilodermatous patches. Although more common on the abdomen, and the proximal and inner parts of the limbs, the lesions may cover the limbs, thorax, neck, and head.

The severity of CGVHD is graded on the extent of skin and other organ involvement following the criteria from the National Institutes of Health consensus.

Expected results of diagnostic studies

Diagnosis is based on the history and physical examination in a bone marrow transplant recipient, supported by histopathology.

In AGVHD, the histopathological findings have been classified into four grades, according to the epidermal damage:

Lichenoid GVHD—histology similar to classic lichen planus: hyperkeratosis, hypergranulosis, acanthosis, and dyskeratotic keratinocytes with basal vacuolar change. Sometimes, sawtoothed rete ridges and dermal melanophages are found. A bandlike infiltrate along the dermal-epidermal junction, occasionally extending to the deep dermis, is essential for the diagnosis, as basal vacuolar changes are a common, long-lasting finding in patients after AHSCT.

Sclerodermoid GVHD—histology indistinguishable from other forms of sclerosis, including lichen sclerosus, morphea, and systemic sclerosis. It may involve the dermis and subcutaneous tissue, and may affect the fascia. The normal tissue is replaced by thick sclerotic collagen fibers and hyalinization of the collagen occurs with loss of the appendage structures.

Diagnosis confirmation

AGVHD

Drug reactions

Drug reactions are mainly due to conditioning chemotherapy in early stages. They could be related to any medication when it appears later in the evolution.

There is a need to combine evaluation of histopathological findings with the clinical presentation to reach a diagnosis. The absence of an inflammatory infiltrate or the presence of eosinophils would suggest a drug reaction, while the presence of hair follicle damage or satellitosis would make the diagnosis of GVHD more likely. It is most difficult to distinguish between toxic epidermal necrolysis and stage IV AGVHD.

- Palmoplantar erythrodysesthesia syndrome can be distinguished only by its clinical presentation: acral dysesthesia, followed by tender erythematous swelling of the palms and soles, which can be bullous, erosive, or ulcerating. It is a frequent and localized side effect related to antineoplastic chemotherapies, most commonly doxorubicin, doctaxel, fluorouracil, and cytarabine.

Histology will show a toxic keratinocyte reaction with sub-basal edema, a tendency to bullae, dilated blood and lymph capillaries, and usually only a mild perivascular lymphocytic infiltration.

Palmoplantar erythrodysesthesia syndrome appears early after the AHSCT due to conditioning therapy. Treatment includes cold compresses or baths.

- Eruption of syringometaplasia develops in patients with AHSCT treated with high-dose chemotherapy regimens. Eruption begins within 2-39 days of initiation of chemotherapy. Well-defined elevated erythematous macular areas develop on the axillae, groin, palms, and soles, and discrete papular lesions form on the trunk or extremities.

Histology will show syringometaplasia. Eruption is asymptomatic and resolves spontaneously without scarring in 7-10 days.

- Toxic epidermal necrolysis is a severe exfoliative adverse drug reaction that is characterized by fever with rapid and extensive epidermal necrolysis. Skin eruptions begin as poorly defined erythematous macules with darker purpuric centers that tend to coalesce and form blisters, leading to extensive epidermal necrosis and detachment. Distribution is usually symmetrical, primarily affecting the face and upper trunk, with mucosal involvement in up to 90% of patients.

The histology will show necrotic keratinocytes and confluent epidermal necrosis with vacuolar alteration of the dermoepidermal junction and subepidermal blisters.

Clinically, toxic epidermal necrolysis may be indistinguishable from stage IV or hyperacute GVHD.

Viral infections

Herpes viruses have a tendency to remain latent in the body after primary infection and periodically reactivate in immunocompromised hosts, including patients after AHSCT.

Infection with herpes simplex virus may occur 1-2 weeks after transplantation, while cytomegalovirus (CMV) infection tends to occur at a median of 38 days after transplantation.

Cutaneous manifestations of viral infections are variable and often indistinguishable from GVHD. Human herpes virus 6 can cause cutaneous symptoms by itself or favor the development of cutaneous AGVHD. Herpes simplex virus may induce erythema multiforme-like lesions in the early days after AHSCT.

Other skin findings include maculopapular eruption, petechiae, vesicullobullous lesions and ulcerations involving the oropharynx and genital tract. Cutaneous disease is a rare manifestation of reactivated CMV, EBV or parvovirus B19 disease but they should be considered.

Changes of acute or chronic radiodermatitis following AHSCT are unusual because of the lower doses of irradiation used in conditioning regimens.

Engraftment syndrome

Engraftment syndrome was first described in patients after autologous hemopoietic stem cell transplantation and after ablative chemotherapy without transplant at the time of neutrophil recovery. It is characterized clinically by fever, rash, and pulmonary injury. Bone marrow engraftment usually occurs between days 12 and 13 after AHSCT.

The clinical findings for engraftment syndrome are very similar to AGVHD. The speed of neutrophil recovery has been seen to be predictive of engraftment syndrome. Major criteria include a temperature greater than 38°C with no identifiable infectious etiology, erythematous exanthem involving more than 25% of body surface area, pulmonary edema, and hypoxia. This eruption usually responds well to corticosteroids.

Systemic sclerosis is in the differential for sclerodermatous GVHD. Histologically, they are indistinguishable, but there is no Raynaud's phenomenon, no Scl-70/anticentromere antibodies, and patients do not present with an edematous phase before the sclerosis in CGVHD.

Who is at Risk for Developing this Disease?

GVHD occurs when immunocompetent donor lymphocytes become sensitized by recipient antigens and react against tissue of the immunosuppressed host.

Requirements of GVHD (Billingham 1966) are that the graft must contain immunologically competent cells, the tissue antigens of the recipient differ from those of donor, and the recipient is immunocompromised.

This condition appears in patients after allogeneic stem cell transplantation. It may occur after solid organ transplantation if a sufficient number of donor cells are in the transplanted organ.

Risks for AGVHD include:

HLA mismatch donor

Matched unrelated donor

Sex-mismatch with donor being female

Older age of donor or recipient

Diagnosis of chronic myeloid leukemia

Increased number of AHSCT procedures

Use of total body radiotherapy

Use of prophylactic treatments other than cyclosporine and methotrexate

More than one stem cell transplant

High IL-3 (Th2 cytokine) levels in donor

Polymorphism of cytokine genes

Ineffective GVHD prophylaxis

Risks for CGVHD include:

Past history of AGVHD, especially greater than grade II

Increased donor or recipient age (age greater than 20 years)

Lack of T cell depletion of the donor stem cells

CMV infection

Female donor to male recipient (previous donor pregnancies)

Transfusion of donor buffy coat

Use of blood stem cells

TBI as conditioning regimen

What is the Cause of the Disease?

Etiology

Pathophysiology

The pathophysiology of AGVHD is divided into three phases:

Conditioning regimen causes tissue damage to the intestinal mucosa (with translocation of microbial products to the circulation) and liver, which leads to activation of host cells and release of inflammatory cytokines. These cytokines upregulate major histocompatibility complex antigens, thus enhancing their recognition by donor T cells.

Donor T cells reactivate and proliferate in response to host antigens, fueled by the inflammatory cytokines.

Chronic GVHD is the result of autoreactive T cells, from donor-derived stem cells. Donor lymphocytes mature in the host thymus and some host-reactive T cells escape from the elimination mechanisms, resulting in persistent alloreactive and autoreactive T-cell clones. These immune dysregulations result in immunodeficiency and autoimmunity. Most patients have evidence of B cell dysregulation with a high prevalence of autoantibodies.

Systemic Implications and Complications

Cutaneous GVHD is usually part of a syndrome with multi-organ involvement, although there are cases of pure cutaneous acute or chronic GVHD.

Skin severity score is independently associated with the risk of nonrelapse mortality (HR 5.2) and with overall mortality (HR 3.4).

Treatment Options

Treatment options in GVHD are an active area of research, as no optimal treatment has been found and morbidity and mortality due to the procedure is relatively high. Most patients will develop multisystemic diseases that require management by multidisciplinary teams.

AGVHD

Treatment focuses on prevention, minimization of risk factors, and the use of AGVHD prophylaxis. A calcineurin inhibitor plus methotrexate or mycophenolate mofetil is the recommended GVHD prophylaxis. Other modalities have been proposed, including total lymphoid irradiation, sirolimus, maraviroc (a CCR5 inhibitor), bortezomib, or vorinostat. New regimens are being developed and tested worldwide in clinical trials.

Optimal Therapeutic Approach for this Disease

Treatment of CGVHD should always be discussed by a multidisciplinary team. They are led by hematologists and include other medical, and sometimes surgical, specialties. Patients usually have multisystemic disease and develop a wide variety of side effects.

AGVHD

It is critical in AGVHD to reach a consensus in the diagnosis of the disease. This usually takes place in an acute/subacute setting, often with only clinical information and minimal laboratory or pathology results. Frequently, therapy is started before a definitive diagnosis can be reached. It is important to exclude infections and drug reactions as causes for the disease.

For systemic disease, the main treatment is to increase the immunosuppressive treatment, initially with corticosteroids. Second-line treatment or salvage therapy is started if disease progresses after 3 days, if there is no change after 7 days, or if the response is incomplete after 14 days of corticosteroid therapy.

First Line

As a first-line therapy, add or increase systemic corticosteroids (up to 2 mg/kg/day of methylprednisolone). Combine a second-line therapy if the patient is already getting high doses of prednisone.

For limited skin disease, use topical corticosteroids (medium-high potency) such as methylprednisolone aceponate, bethametasone dipropionate, or clobetasol. Systemic steroids (as in systemic AGVHD), other immunosuppressants, ECP, PUVA, and UVB (broad or narrow band) may also be used.

CGVHD

For systemic disease, a combination of corticosteroids (1 mg/kg) and cyclosporine (10 mg/kg, maintain serum levels 150-300 ng/mL) is the recommended first line of therapy.

Patient Management

A multidisciplinary team should manage patients.

Patients with AGVHD are usually inpatients, and should be reviewed very often to assess clinical changes.

Patients with CGVHD are followed in outpatient clinics. Regular follow-ups (every 4-8 weeks) are required to assess clinical changes. Involvement of other organs (joints, eyes, liver, lungs, gut, etc.) should be assessed on a regular basis.

Unusual Clinical Scenarios to Consider in Patient Management

Clinicians must be mindful of the differential diagnosis of acute GVHD prior to establishing this diagnosis.

It has been suggested that systemic corticosteroid therapy should be started as soon as possible, regardless of the histopathology result.

What is the Evidence?

(This comprehensive review provides a synopsis of clinical manifestations of acute, lichenoid, and sclerodermatous phases of GVHD with a look at the current evidence surrounding its differential diagnosis and the new manifestations of GVHD.)

(This review describes established state-of-the-art stem cell transplantation. Some new developments include peripheral blood stem cell compared to bone marrow enhanced engraftment and the role of reduced conditioning.)